Coronary heart disease (CHD), also known as atherosclerotic heart disease, is caused by plaque being deposited and building up along the inner walls of the arteries of the heart. The risk of arteries narrowing increases with smoking, insufficient exercise, obesity, diabetes, high blood pressure, and dyslipidemia. CHD is the leading cause of death irrespective of sex and accounts for approximately 500,000 deaths in the United States every year out of 15.8 million CHD patients.
According to the guidelines of NCEP (National Cholesterol Education Program) ATP-III (Adult Treatment Panel III), management of blood cholesterol levels is very important for the prevention or improvement of CHD. NCEP classified persons with CHD history or CHD-equivalent risk factors into three groups according to the 10-year risk of CHD onset (<10%, 10-20%, >20%), and proposed criteria/goals of living behavior improvement and drug treatment for reducing LDL-cholesterol levels in each group (JAMA 2001; 285: 2486-2497, AAOHN J 2002; 50: 360-364, Vascular Medicine 2002; 7: 187-194). 3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, such as statins, are reported to lower blood cholesterol levels by inhibiting the synthesis of cholesterol and increasing the expression of LDL receptors, and make a contribution to the treatment or prevention of cardiovascular diseases irrespective of sex and age by reducing the incidence of cardiac diseases by as high as approximately 30% (Lancet 1994; 344: 1383-1389, Lancet 2002; 360: 7-22, Lancet 2004; 364: 7-22, JAMA 1999; 282: 2340-2346). However, these statin-lineage drugs are not sufficiently efficacious for the treatment or prevention of atherosclerosis-caused CHD.
Since the report that the incidence risk of CHD increases with a decrease in HDL cholesterol level (N. Engl. J. Med. 1976; 294: 293-298, Lancet. 1977; 1: 965-968, Am. J. Med. 1977; 62: 707-714), HDL cholesterol-increasing drugs such as fibrate or niacin have been developed (Vasc Med 2002; 7: 187-194, JAMA 2001; 285: 2486-2497). Particularly, as HDL was revealed to have various functions including the inhibition of LDL oxidation (Free Radic. Biol. Med. 41: 1031-1040), anti-thrombotic/anti-inflammatory activity (Circ. Res. 98: 1352-1364, Arterioscler. Thromb. Vasc. Biol. 15: 1987-1994), and the prevention and improvement of arteriosclerosis (Circulation. 100: 1816-1822) as well as reverse cholesterol transport, the use of HLD cholesterol-increasing drugs alone or in combination with statins has been expected as a novel therapy for CHD. However, this therapy is reported to produce a safety problem such as drug resistance, and its efficacy is, in fact, not as high as expected. Therefore, there is a need for more potent HDL cholesterol-increasing drugs.
In response to this need, CETP (cholesterylester transfer protein) inhibitors have been developed as HDL cholesterol-increasing agents with a novel mechanism. CETP is a hydrophobic glycoprotein which circulates mostly in association with HDL in blood (Tall A R et al., J Lipid Res. 1993; 34: 1255-1274). This plasma protein performs a homoexchange by collecting triglycerides from very low density lipoprotein (VLDL) and LDL, and exchanges them for cholesteryl esters from HLD, thus contributing to the re-distribution of cholesterols and the remodeling of lipoproteins. Consistent with this in vivo activity of CETP, it is reported that blood HDL cholesterol levels decrease with an increase in blood CETP activity (Curr Opin. Lipidol. 11; 4: 389-396). Also, decreased CETP activity brings about an increase in HDL cholesterol levels which, in turn, facilitate reverse cholesterol transport, resulting in a preventive arteriosclerosis effect (Philip J et al., Arterioscler Thromb Vasc Biol. 2003; 23: 160-167). The suggestion of the improvement of HDL cholesterol through CETP inhibition has incited pharmaceutical companies to develop drugs for preventing or treating CHD, including anacetrapib of Merck, torcetrapib of Pfizer, and dalcetrapib of Roche. During clinical trials, torcetrapib was first to be dropped due to safety problems, followed by dalcetrapib due to its weak inhibitory activity against CETP and insufficient clinical efficacy.
Therefore, there is an urgent need for a CETP inhibitor that is safes and more potent, allowing for the development of a drug for preventing or treating CHD with excellent efficacy.